Pteridinone derivatives as PI3-kinases inhibitors

Table 1

Preparation of 2-(3-(2-hydroxyethylsulfonyl)phenylamino)-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-one

2-Chloro-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (150 mg; 0.623 mmol) and 2-(3-Amino-phenylsulfonyl)-ethanol (120 mg; 0.600 mmol) were heated to 160° C. for 30 minutes. The reaction mixture was then suspended in dichloromethane and ethyl acetate then filtrated to yield 215 mg (0.530 mmol; 85% yield) as yellow solid.

Preparation of methanesulfonic acid 2-[3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-benzenesulfonyl]-ethyl ester

2-(3-(2-Hydroxyethylsulfonyl)phenylamino)-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-one (1.45 g; 3.576 mmol) was dissolved in 35 mL dichloromethane, ethyldiisopropylamine (0.92 mL; 5.360 mmol) and 4-dimethylaminopyridine (cat.) were added. Then the mixture was cooled to 0° C. and mesylchloride (0.332 ml; 4.290 mmol) was added slowly. The reaction mixture was allowed to get to room temperature and after 4 h water was added and the mixture was extracted with dichloromethane. Drying of the organic layer with sodium sulphate and removal of the solvents gave 1.1 g (2.275; 63% yield) of intermediate the desired product as foam.

Analytical Methods

Preparative HPLC-MS Methods

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Synthesis of Compounds of Formula 1

Table 1

2-Chloro-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (20 mg; 0.083 mmol) and 3-(methylsulfonyl)-5-trifluoromethyl-phenylamine (19.8 mg; 0.083 mmol) were dissolved in 0.1 ml of 1,4-dioxane, 0.1 ml of water and 10 μl of HCl 37%. The reaction mixture was irradiated in a microwave reactor (OEM; 200 W, ramp 5 min.; hold 20 min.; 200° C.; 150 psi). The reaction mixture was diluted with dichloromethane and treated with scavenger resin PS-CHO in order to remove the un-reacted primary aniline. After 1 h, the organic phase was filtered and concentrated in vacuo. The crude was treated with isopropyl ether and the precipitate obtained was filtered and dried in vacuo. 10 mg (0.024 mmol; 28% yield) of the desired compound were obtained.

LC-MS method: Gradient — 2

Retention time: 7.78 min

[M+H]=444

The following example was prepared with the same procedure described for the preparation of Example 1 and reported in Scheme 6.

Table 1

Starting from 2-chloro-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (45 mg; 0.175 mmol) and 3-(5-cyclopropyl-1H-pyrazol-3-yl)-5-(methylsulfonyl)-aniline (49 mg; 0.158 mmol), 6 mg (0.012 mmol; 7% yield) of the desired compound were obtained.

LC-MS method: A

Retention time: 6.65 min

[M+H]=482

Table 1

1,1′-Carbonyldiimidazole (40 mg; 0.244 mmol) was added to a warmed (50° C.) suspension of 3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-trifluoromethyl-benzoic acid (50 mg; 0.122 mmol). The reaction mixture was maintained at that temperature for 6 h, then methylamine (2M solution in THF; 0.305 ml; 0.611 mmol) was added. The reaction mixture was maintained to 50° C. overnight. The reaction mixture was diluted with dichloromethane and washed with water. The organic phase was separated and dried on a phase separator and concentrated. The crude was treated with isopropyl ether/acetone and the precipitate obtained was filtered and dried in vacuo. 25 mg (0.059 mmol; 48% yield) of the desired compound were obtained.

LC-MS method: G

Retention time: 5.28 min

[M+H]=423

The following examples were prepared with the same procedure described for the preparation of Example 3 and reported in Scheme 7.

Table 1

Starting from 3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-methanesulfonylamino-benzoic acid (40 mg; 0.0.092 mmol) and 4-(aminomethyl)-pyridine (0.05 ml; 0.46 mmol), 14 mg (0.027 mmol; 29% yield) of the desired compound were obtained.

LC-MS method: Gradient — 2

Retention time: 5.03 min

[M+H]=525

Table 1

Starting from 3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-benzoic acid (80 mg; 0.092 mmol) and N,N-dimethyl-1,3-propanediamine (0.120 ml; 0.954 mmol), 44 mg (0.087 mmol; 46% yield) of the desired compound were obtained.

LC-MS method: Gradient

Retention time: 3.11 min

[M+H]=504

Table 1

3-(8-Isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-benzamide (100 mg; 0.239 mmol) (prepared as described in Example 28) was diluted in 1 ml of dry DMF and, under nitrogen atmosphere, phosphorous oxychloride (0.55 ml; 0.597 mmol) was added. The reaction was warmed to 80° C. overnight. Then, it was cooled to room temperature, diluted with dichloromethane and washed with saturated bicarbonate solution. The organic phase was separated and dried on a phase separator and concentrated. The crude was treated with isopropyl ether/methanol. 74.5 mg (0.186 mmol; 78% yield) of the desired compound were obtained.

LC-MS method: E

Retention time: 4.21 min

[M+H]=401

Table 1

2-(3-Amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (50 mg; 0.128 mmol), sodium triacetoxyborohydride (40 mg; 0.192 mmol) and methylethylketone (0.011 ml; 0.128 mmol) were dissolved in 2 ml of dichloromethane. The reaction mixture was stirred at room temperature overnight, it was then diluted with dichloromethane and washed with saturated sodium bicarbonate solution, filtered on phase separator and concentrated. The crude was purified with HPLC-MS preparative method D. 12.4 (0.072 mmol; 58% yield) of the desired compound were obtained.

LC-MS method: E

Retention time: 5.34 min

[M+H]=447

Table 1

Example 42 was prepared with the same procedure described for the preparation of Example 41 starting from 2-(3-amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (45 mg; 0.115 mmol and (4-oxo-cyclohexyl)-carbamic acid tert-butyl ester (122 mg; 0.576 mmol). 6 mg (0.012 mmol; 11% yield) of the desired compound were obtained.

LC-MS method: L

Retention time: 2.1/min

[M+H]=488

Preparation of 1-(2-chloro-ethyl)-3-[3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-methylsulfonyl-phenyl]urea

2-(3-Amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (300 mg; 0.768 mmol) was diluted under nitrogen atmosphere in 3 ml of dry 1,4-dioxane, then a solution of 2-chloroethyl-isocyanate (0.09 ml; 0.999 mmol) in 2 ml of dry 1,4-dioxane was added drop-wise. The reaction mixture was stirred at room temperature for 3 h, then warmed to 60° C. and maintained at that temperature for 3 h. The reaction mixture was then concentrated in vacuo. The crude obtained was treated with isopropyl ether. The solid obtained was filtered. 261 mg (0.001 mol; 68.5 yield) of the desired compound were obtained.

Table

1-(2-Chloro-ethyl)-3-[3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-urea (250 mg; 0.504 mmol) and Cesium carbonate (224 mg; 0.655 mmol) were diluted under nitrogen atmosphere in 15 ml of dry acetonitrile. The reaction mixture was warmed to 60° C. and stirred at that to temperature for 2 h. A formation of a solid was observed. It was filtered, washed with water and dried in vacuo. 75 mg (0.163 mmol; 32% yield) of the desired compound were obtained.

LC-MS method: A

Retention time: 4.3 min

[M+H]=460

Table 1

2-(3-Amino-5-methanesulfonyl-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (40 mg; 0.102 mmol) was dissolved in 1 ml of dry dichloromethane. Triethylamine (0.027 ml; 0.205 mmol) was added and the reaction mixture was cooled to 0° C. Phenylacetylchloride (0.016 ml; 0.123 mmol) in 0.5 ml of dry dichloromethane was added drop-wise. The reaction mixture was allowed to reach room temperature and then warmed to 40° C. 1 ml of dry DMF was added in order to increase solubilization and the reaction mixture was stirred at 40° C. for 2 h. The reaction mixture was then diluted with dichloromethane and washed with saturated sodium bicarbonate solution, the organic phase was filtered on a phase separator and concentrated. The crude was purified with HPLC-MS preparative method E. 7.1 mg (0.014 mmol; 14% yield) of the desired compound were obtained.

LC-MS method: G

Retention time: 6.23 min

[M+H]=509

Table 1

(R)-2-phenylpropionic acid (0.026 ml; 0.192 mmol), TBTU (65.7 mg; 0.205 mmol) DIPEA (65 ul; 0.384 mmol) in 1 ml of DMF were stirred at room temperature for 30 min. 2-(3-Amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (50 mg; 0.128) was added and the reaction mixture was warmed to 50° C. overnight. The reaction mixture was diluted with dichloromethane and washed with water. The organic phase was filtered on a phase separator, and 50 mg of a PS-CHO scavenger resin were added. The organic phase was stirred overnight, then the resin was filtered and the organic phase concentrated. The crude obtained was purified with HPLC-MS preparative method B. 32 mg (0.063 mmol; 49% yield) of the desired compound were obtained.

LC-MS method: I

Retention time: 5.97 min

[M+H]=523

The following examples were prepared with the same procedure described for the preparation of Example 45 and reported in Scheme 10.

Table 1

Starting from 3-methyl-5-isoxazole-acetic acid 21.6 mg; 0.154 mmol) and 2-(3-amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (40 mg; 0.102), 40.6 mg (0.079 mmol; 77% yield) of the desired compound were obtained.

LC-MS method: A

Retention time: 4.7 min

[M+H]=514

Table 1

Starting from m-tolyl-acetic acid (23.08 mg; 0.154 mmol) and 2-(3-amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (40 mg; 0.102), 51.6 mg (0.099 mmol; 96% yield) of the desired compound were obtained.

LC-MS method: A

Retention time: 6.93 min

[M+H]=523

Table 1

8-Isopropyl-2-(3-(methylsulfonyl)-5-methylamino-phenylamino)-5-methyl-7,8-dihydro-5H-pteridin-6-one (30 mg; 0.074 mmol) was dissolved in 1 ml of dry 1,4-dioxane. Triethylamine (0.04 ml; 0.304 mmol) was added and the reaction mixture was cooled to 0° C. Phenylacetylchloride (0.014 ml; 0.111 mmol) in 0.5 ml of dry 1,4-dioxane was added drop-wise. The reaction mixture was allowed to reach room temperature and then warmed to 40° C. for 2 h. Phenylacetylchloride (0.014 ml; 0.111 mmol) in 0.5 ml of dry 1,4-dioxane was added drop-wise again and the reaction mixture stirred at 40° C. for overnight. The reaction mixture was then to diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was filtered on a phase separator and concentrated. The crude was purified with HPLC-MS preparative method A. 13 mg (0.025 mmol; 33.5% yield) of the desired compound were obtained.

LC-MS method: E

Retention time: 5.54 min

[M+H]=523

Table 1

8-Isopropyl-2-(3-(methylsulfonyl)-5-methylamino-phenylamino)-5-methyl-7,8-dihydro-5H-pteridin-6-one (30 mg; 0.074 mmol) and 3-methyl-5-isoxazoleacetic acid (10.4 mg; 0.074 mmol), were dissolved in 1 ml of dry dichloromethane. The reaction mixture was cooled to 0° C. and N,N′-dicyclohexylcarbodiimide (37.18; 0.185 mmol) in 1 ml of dry dichloromethane was added drop-wise. The reaction mixture was allowed to reach room temperature and maintained at room temperature for 48 h. The precipitated formed was filtered and the solution concentrated in vacuo. The crude was treated with hexane/isopropyl ether and the solid filtered and dried in vacuo. 39 mg (0.074 mmol; 99% yield) of the desired compound were obtained.

LC-MS method: Purification method B

Retention time: 5.9 min

[M+H]=528

Preparation of (R)-3-[3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenylcarbamoyl]-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

(R)-3-carboxymethyl-pyrrolidine-1-carboxylic acid tert butyl ester (132 mg; 0.576 mmol), TBTU (197 mg; 0.615 mmol) DIPEA (197 ul 1.15 mmol) in 5 ml of DMF were stirred at room temperature for 30 min. 2-(3-Amino-5-methanesulfonyl-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (150 mg; 0.384 mmol) was added and the reaction mixture was warmed to 50° C. overnight. The reaction mixture was diluted with dichloromethane and washed with water. The to organic phase was dried on MgSO 4 , concentrated in vacuo and the crude obtained treated with (iPr) 2 O and acetone. The solid obtained was filtered and dried in vacuo. 195 mg (0.324 mmol; 84% yield) of the desired compound were obtained.

Preparation of (S)-3-[[3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenylcarbamoyl]-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

The (S)-enantiomer was prepared with the same procedure used for the (R)-enantiomer and described in Scheme 12 starting from (S)-3-carboxymethyl-pyrrolidine-1-carboxylic acid tert butyl ester (132 mg; 0.576 mmol) and 2-(3-Amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (150 mg; 0.384 mmol), 190 mg (0.316 mmol; 82% yield) of product were obtained.

The following carboxylic acid tert-butyl esters were prepared with the same procedure described for the preparation of (R) and (S)-3-[[3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenylcarbamoyl]-methyl]-pyrrolidine-1-carboxylic acid tert-butyl esters and reported in Scheme 12.

Preparation of (R)-3-[3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

Starting from (R)-Pyrrolidine-1,3-dicarboxylic acid tert butyl ester (165 mg; 0.768 mmol) and 2-(3-amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (150 mg; 0.384 mmol), 27 mg (0.046 mmol; 12% yield) of the desired compound were obtained.

Preparation of (S)-3-[3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

The (S)-enantiomer was prepared with the same procedure used for the (R)-enantiomer and described in Scheme 12 starting from (S)pyrrolidine-1,3-dicarboxylic acid tert butyl ester (33 mg; 0.154 mmol) and 2-(3-amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (40 mg; 0.102 mmol), 19 mg (0.032 mmol; 32% yield) of the desired compound were obtained.

Preparation of (R)-2-[3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

Starting from (R)pyrrolidine-1,2-dicarboxylic acid tert butyl ester (74 mg; 0.346 mmol) and 2-(3-amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (90 mg; 0.230), 40 mg (0.068 mmol; 29.5% yield) of the desired compound were obtained.

Preparation of (S)-2-[3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

The (S)-enantiomer was prepared with the same procedure used for the (R)-enantiomer and described in Scheme 12 starting from (S)pyrrolidine-1,2-dicarboxylic acid tert butyl ester (44 mg; 0.204 mmol) and 2-(3-amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (40 mg; 0.102), 15.2 mg (0.026 mmol; 25.2% yield) of the desired compound were obtained.

Preparation of (R)-3-[3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester

Starting from (R)-piperidine-1-3-dicarboxylic acids 1-tert-butyl ester (70 mg; 0.307 mmol) and 2-(3-amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (80 mg; 0.205 mmol), 46 mg (0.076 mmol; 37% yield) of the desired compound were obtained.

Preparation of (S)-3-[3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester

The (S)-enantiomer was prepared with the same procedure used for the (R)-enantiomer and described in Scheme 12 starting from (S)-piperidine-1-3-dicarboxylic acids 1-tert-butyl ester (70 mg; 0.307 mmol) and 2-(3-amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (80 md; 0.205 mmol), 100 mg (0.166 mmol; 81% yield) of the desired compound were obtained.

Preparation of 2-[3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester

Starting from piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (176 mg; 0.768 mmol) and 2-(3-amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (200 mg; 0.512 mmol), 45 mg (0.074 mmol; 15% yield) of the desired compound were obtained.

Preparation of 2-[3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenylcarbamoyl]-morpholine-4-carboxylic acid tert-butyl ester

Starting from morpholine-2,4-dicarboxylic acid 4-tert-butyl ester (70 mg; 0.307 mmol) and 2-(3-amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (80 md; 0.205 mmol), 70 mg (0.116 mmol; 57% yield) of the desired compound were obtained.

Table 1

(R)-3-[[3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenylcarbamoyl]-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (180 mg; 0.299 mmol) was diluted in 4 ml of 4M HCl in 1,4-dioxane and to stirred for 6 h. The reaction mixture was concentrated in vacuo. The free amine was obtained after loading the corresponding hydrochloride on a SCX-cartridge and recovering with MeOH/ammonia solution. 130 mg (0.259 mmol; 87% yield) of the desired compound were obtained.

LC-MS method: C

Retention time: 4.23 min

[M+H]=502

The following example was prepared with the same procedure described for the preparation of example 78 and reported in Scheme 12.

Table 1

Starting from (S)-2-[3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (10 mg; 0.017 mmol), 8 mg (0.015 mmol; 90% yield) of the desired compound were obtained.

LC-MS method: A

Retention time: 5.18 min

[M+H]=488

Table 1

N-[3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-2-(S)-pyrrolidin-3-yl-acetamide (40 mg; 0.080 mmol), sodium triacetoxyborohydride (34 mg; 0.159 mmol) and cyclopentanone (0.035 ml; 0.399 mmol) were mixed in 5 ml of dichloromethane. The reaction mixture was stirred at 40° C. overnight.

The reaction mixture was diluted in dichloromethane/methanol. The solid obtained after loading the reaction mixture on a SCX-cartridge and recovering with MeOH/ammonia solution was treated with methanol/isopropyl ether. The precipitate was filtered and dried in vacuo. 32 mg (0.056 mmol; 70% yield) of the desired compound were obtained.

LC-MS method: A

Retention time: 6.48 min

[M+H]=570

The following examples were prepared with the same procedure described for the preparation of example 91 and reported in Scheme 12.

Table 1

Starting from N-[3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-2-(S)-pyrrolidin-3-yl-acetamide (45 mg; 0.090 mmol), 32.8 mg (0.057 mmol; 64% yield) of the desired compound were obtained.

LC-MS method: A

Retention time: 6.69 min

[M+H]=570

Table 1

Starting from (S)-pyrrolidine-2-carboxylic acid [3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-amide (33 mg; 0.063 mmol). 16.8 mg (0.030 mmol; 48% yield) of the desired compound were obtained.

LC-MS method: A

Retention time: 5.1 min

[M+H]=556

Preparation of [(R)-[3-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenylcarbamoyl]-phenyl-methyl]-carbamic acid tert-butyl ester

(R)-Tert-butoxycarbonylamino-phenyl-acetic acid (36 mg; 0.154 mmol), TBTU (53 to mg; 0.164 mmol) DIPEA (52 ul; 0.307 mmol)) in 1 ml of DMF were stirred at room temperature for 30 min. 2-(3-Amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (40 mg; 0.102) was added and the reaction mixture was warmed to 50° C. overnight. The reaction mixture was diluted with dichloromethane and washed with water. The organic phase was filtered on a phase separator and, concentrated. The crude obtained treated with (iPr) 2 O and acetone. The solid obtained was filtered and dried in vacuo. 18 mg (0.029 mmol; 28% yield) of the desired compound were obtained.

Preparation of [(R)-cyclohexyl-[ 3 -(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenylcarbamoyl]-methyl]-carbamic acid tert-butyl ester

Starting from (R)-tert-butoxycarbonylamino-cyclohexyl-acetic acid (31.6 mg; 0.123 mmol) and 2-(3-amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (40 mg; 0.102), 11.3 mg (0.018 mmol; 17.5% yield) of the desired compound were obtained.

Table 1

[(R)-[3-Isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenylcarbamoyl]-phenyl-methyl]-carbamic acid tert-butyl ester (18 mg; 0.029 mmol) was diluted in 1 ml of 4M HCl in 1,4-dioxane and stirred for 6 h. The organic phase was concentrated and the solid dried in vacuo. 14.2 mg (0.027 mmol; 94% yield) of the desired compound were obtained.

LC-MS method: A

Retention time: 5.59 min

[M+H]=524

Table 1

[(R)-Cyclohexyl-[3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-methylsulfonyl-phenylcarbamoyl]-methyl]-carbamic acid tert-butyl ester (11 mg; 0.018 mmol) was diluted in 1 ml of 4M HCl in 1,4-dioxane and stirred for 6 h. The organic phase was concentrated and the solid dried in vacuo. 9 mg (0.017 mmol; 95% yield) of the desired compound were obtained.

LC-MS method: C

Retention time: 4.93 min

[M+H]=530

Table 1

[3-(8-Isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-thiocarbamic acid ethyl ester (50 mg; 0.104 mmol) was dissolved in 1 ml of dry DMF. A solution of methylamine (2M in THF; 0.104 ml; 0.209 mmol) was added. The reaction mixture was stirred at 70° C. overnight, then it was diluted with dichloromethane and washed with water. The organic phase was filtered on a phase separator and concentrated. The crude was treated with isopropyl ether/ethanol. The precipitated formed was filtered and dried in vacuo. 12 mg (0.017 mmol; 95% yield) of the desired compound were obtained.

LC-MS method: G

Retention time: 3.57 min

[M+H]=448

The following examples were prepared with the same procedure described for the preparation of example 97 and reported in Scheme 14.

Table 1

Starting from [3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-thiocarbamic acid ethyl ester (40 mg; 0.084 mmol) and (S)-tetrahydrofurfurylamine (16.9 mg; 0.167 mmol), 22.2 mg (0.043 mmol; 51% yield) of the desired compound were obtained.

LC-MS method: B

Retention time: 5.77 min

[M+H]=518

Table 1

Starting from [3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-thiocarbamic acid ethyl ester (40 mg; 0.084 mmol), (S)-cyclopentyl-pyrrolidin-3-ylamine di-hydrochloride (38 mg; 0.167 mmol) and triethylamine (0.023; 0.176 mmol), 11.2 mg (0.020 mmol; 23.5% yield) of the desired compound were obtained.

LC-MS method: E

Retention time: 4.87 min

[M+H]=571

Table 1

Starting from [3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-thiocarbamic acid ethyl ester (40 mg; 0.084 mmol) and (S)-1-benzyl-3-aminopyrrolidine (0.029 ml; 0.167 mmol), 35.9 mg (0.061 mmol; 72.5% yield) of the desired compound were obtained.

LC-MS method: B

Retention time: 4.66 min

[M+H]=593

Table 1

(S)-1-Cyclopentyl-pyrrolidin-3-ylamine (53 mg; 0.237 mmol) was dissolved in 1 ml of dry DMF. 1,1′-Carbonyldiimidazole (70 mg; 0.436 mmol) and diisopropylethylamine (0.044 ml; 0.257 mmol) were added. The reaction mixture was warmed to 70° C., then, 8-isopropyl-2-(3-(methylsulfonyl)-5-methylamino-phenylamino)-5-methyl-7,8-dihydro-5H-pteridin-6-one (80 mg; 0.198 mmol) was added. The reaction mixture was stirred at 70° C. overnight. The reaction mixture was concentrated and the crude was purified with HPLC_MS preparative method C. 16 mg (0.027 mmol; 14% yield) of the desired compound were obtained.

LC-MS method: A

Retention time: 4.21 min

[M+H]=585

Table 1

Following the same procedure used for ex. 128, starting from (S)-1-benzyl-3-amino-pyrrolidine (41 mg; 0.237 mmol) and 8-isopropyl-2-(3-(methylsulfonyl)-5-methylamino-phenylamino)-5-methyl-7,8-dihydro-5H-pteridin-6-one (80 mg; 0.198 mmol), 2 mg (0.003 mmol; 2% yield) of the desired compound were obtained.

LC-MS method: A

Retention time: 4.33 min

[M+H]=607

Preparation of (4-[3-[3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-ureido]-cyclohexyl)-carbamic acid tert butyl ester

[3-(8-Isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-thiocarbamic acid ethyl ester (150 mg; 0.313 mmol) was dissolved in 1 ml of dry DMF, tert-butyl-cis-4-aminocyclohexylcarbamate (201 mg; 0.940 mmol) was added. The reaction mixture was stirred at 70° C., overnight, then, it was diluted with water. The precipitated formed was filtered, washed with water and dried in vacuo. 196 mg (0.311 mmol; 99% yield) of the desired compound to were obtained.

Table 1

4-[3-[3-(8-Isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-ureido]-cyclohexyl)-carbamic acid tert butyl ester (25 mg; 0.040 mmol) was diluted in 1 ml of 1,4-dioxane (4M HCl) and stirred for 6 h.

The organic phase was concentrated. The free amine was obtained after loading the corresponding hydrochloride on a SCX-cartridge and recovering with MeOH/ammonia solution. The crude obtained was treated with isopropyl ether, filtered and dried in vacuo. 19 mg (0.036 mmol; 90% yield) of the desired compound were obtained.

LC-MS method: A

Retention time: 4.14 min

[M+H]=531

Table 1

1-(4-Amino-cyclohexyl)-3-[3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-urea (40 mg; 0.075 mmol), sodium triacetoxyborohydride (31 mg; 0.150 mmol) and formaldehyde (0.030 ml; 0.375 mmol) were dissolved in 5 ml of dry dichloromethane and the reaction mixture was stirred at 40′° C. overnight. Sodium triacetoxyborohydride (31 mg; 0.150 mmol) and formaldehyde (0.030 ml; 0.375 mmol) were added again to increase the conversion and the reaction mixture was stirred at 40° C. overnight. The reaction mixture was cooled to room temperature, diluted with dichloromethane/methanol to and loaded on a SCX-cartridge. The free amine was obtained after loading the corresponding hydrochloride on a SCX-cartridge and recovering with MeOH/ammonia solution. The crude obtained was treated with isopropyl ether/acetone, the precipitate filtered and dried in vacuo. 31.4 mg (0.056 mmol; 75% yield) of the desired compound were obtained.

LC-MS method: A

Retention time: 5.5 min

[M+H]=559

Preparation of (R)-2-[3-[3-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-ureidomethyl]-pyrrolidine-1-carboxylic acid tert butyl ester

[3-(8-Isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-thiocarbamic acid ethyl ester (500 mg; 1.045 mmol) was dissolved in 2 ml of dry DMF. (R)-2-(aminomethyl)-pyrrolidine-1-carboxylic acid to tert-butyl ester (418 mg; 2.089 mmol) was added. The reaction mixture was stirred at 70° C., overnight, then, it was diluted with water/methanol. The precipitated formed was dried in vacuo. 570 mg (0.924 mmol; 88.5% yield) of the desired compound were obtained.

Preparation of (S)-2-[3-[3-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-ureidomethyl]-pyrrolidine-1-carboxylic acid tert butyl ester

The (S)-enantiomer was prepared following the same procedure used for the (R)-enantiomer and described in scheme 17 starting from [3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-thiocarbamic acid ethyl ester (500 mg; 1.045 mmol) and (S)-2-(aminomethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (418 mg; 2.089 mmol). 500 mg (0.783 mmol; 75% yield) of the desired compound were obtained.

Table 1

(R)-2-[3-[3-8-Isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-ureidomethyl]-pyrrolidine-1-carboxylic acid tert butyl ester (570 mg; 0.939 mmol) was dissolved in 10 ml of methanol and 1 ml of HCl 37% were added. The reaction mixture was stirred at room temperature overnight, then it was concentrated in vacuo. The crude was diluted in dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was filtered on a phase separator, concentrated in vacuo. The crude was treated with isopropyl ether/methanol, filtered and dried in vacuo. 200 mg (0.387 mmol; 37% yield) of the desired compound were obtained.

LC-MS method: E

Retention time: 3.1 min

[M+H]=517

Table 1

1-[3-[3-8-Isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-3-(R)-1-pyrrolidin-2-ylmethyl-urea (50; 0.097 mol) was dissolved in 1 ml of dichloromethane and sodium triacetoxyborohydride (41 mg; 0.194 mmol) was added. Cyclopentanone (0.042 ml; 0.484 mmol) was added to the reaction mixture. The reaction mixture was maintained at room temperature overnight, then it was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was filtered on a phase separator and concentrated. The crude was purified with HPLC-MS preparative method B. 15.5 mg (0.027 mmol; 27% yield) of the desired compound were obtained.

LC-MS method: I

Retention time: 4.84 min

[M+H]=585

Preparation of (R)-3-[3-[3-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-ureidomethyl]-pyrrolidine-1-carboxylic acid tert butyl ester

[3-(8-Isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-thiocarbamic acid ethyl ester (500 mg; 1.045 mmol) was dissolved in 2 ml of dry DMF. (R)-3-(Aminomethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (418 mg; 2.089 mmol) was added. The reaction mixture was stirred at 70° C., overnight, then, it was diluted with water/methanol. The precipitated formed was dried in vacuo. 600 mg (0.973 mmol; 93% yield) of the desired compound were obtained.

Preparation of (S)-3-[3-[3-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-ureidomethyl]-pyrrolidine-1-carboxylic acid tert butyl ester

The (S)-enantiomer was prepared following the same procedure used for the (R)-enantiomer and described in scheme 18 starting from [3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-thiocarbamic acid ethyl ester (500 mg; 1.045 mmol) and (S)-3-(aminomethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (418 mg; 2.089 mmol). 600 mg (0.973 mmol; 93% yield) of the desired compound were obtained.

The carboxylic acid tert butyl esters reported in Scheme 18 were prepared following the same procedure described for the preparation of (R)- and (S)-3-[3-[3-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-ureidomethyl]-pyrrolidine-1-carboxylic acid tert butyl esters.

Table 1

(R)-3-[3-[3-8-Isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-ureidomethyl]-pyrrolidine-1-carboxylic acid tert butyl ester (900 mg; 1.459 mmol) was diluted in 10 ml of methanol and 1 ml of HCl 37% were added. The reaction mixture was stirred at room temperature overnight, then it was concentrated in vacuo. The crude was diluted in dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was filtered on a phase separator, concentrated in vacuo. The crude was treated with isopropyl ether/methanol, filtered and dried in vacuo. 300 mg (0.581 mmol; 40% yield) of the desired compound were obtained.

LC-MS method: E

Retention time: 3.05 min

[M+H]=517

Table 1

(R)-1-Cyclopentyl-pyrrolidin-3-ol hydrochloride (39 mg; 0.251 mmol) was suspended in 3 ml of NMP, and NaH (10 mg; 0.263 mmol) was added. The reaction mixture was stirred at room temperature for 15 min, then, [3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-yl-amino)-5-(methylsulfonyl)-phenyl]-thiocarbamic acid ethyl ester (60 mg; 0.125 mmol) was added. The reaction mixture was stirred at 70° C. for 5 min. The reaction mixture was diluted with dichloromethane and washed with water. The organic phase was filtered on a Phase separator, treated with a PS-CHO scavenger resin, filtered again and concentrated. The crude obtained was treated with isopropanol and the precipitate formed was filtered and dried in vacuo. 22.5 mg (0.039 mmol; 31% yield) of the desired compound were obtained.

LC-MS method: C

Retention time: 5 min

[M+H]=572

Table 1

Following the same procedure described for ex. 135, starting from (S)-1-cyclopentyl-pyrrolidin-3-ol hydrochloride (39 mg; 0.251 mmol) and [3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-5-(methylsulfonyl)-phenyl]-thiocarbamic acid ethyl ester (60 mg; 0.125 mmol), 24 mg (0.042 mmol; 33.5% yield) of the desired compound were obtained.

LC-MS method: A

Retention time: 3.41 min

[M+H]=572

Table 1

3-Amino-5-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-benzenesulfonamide (40 mg; 0.104 mmol) was suspended in 0.5 ml of dry to pyridine. The reaction mixture was cooled to 0° C. and 4-fluorobenzenesulfonylchloride (29.8 mg; 0.153 mmol) was added. The reaction mixture was allowed to reach room temperature and maintained at this temperature overnight. The reaction mixture was diluted with dichloromethane and washed with water. The organic phase was separated and dried on a phase separator and concentrated. The crude was purified with HPLC-MS preparative method B. 7.6 mg (0.014 mmol; 52% yield) of the desired compound were obtained.

LC-MS method: A

Retention time: 4.93 min

[M+H]=550

Table 1

Methanesulfonic acid 2-[3-(8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-benzenesulfonyl]-ethyl ester (130 mg; 0.269 mmol) was dissolved in 2.5 mL dimethylformamide and methylamine hydrochloride (54 mg; 0.807 mmol) was added. The reaction mixture was stirred at room temperature for 4 h. Then, the mixture was concentrated and dissolved in water and dichloromethane. The organic layer was dried with sodium sulphate then concentrated and crystallized from ether to yield 69 mg (0.165 mmol; 61% yield) of the desired product as a yellow solid.

LC-MS method: M

Retention time: 0.79 min

[M+H]=419

Some compounds which may be prepared by one of the methods of synthesis described above are hereinafter listed by way of example. All the melting points (m p ) are given in ° C.:. In order to determine the inhibitory activity of the compounds on PI3Kγ, an in-vitro kinase assay is set up which is based on the transfer of the terminal γ-phosphate of ATP to phosphatidylinositol-4,5-bisphosphate (PIP 2 ). The enzyme activity used is the Gβ 1 γ 2 -His stimulated PI3Kγ. The expression and purification of Gβ 1 γ 2 -His and p101-GST/p110γ from Sf9-cells ( Spodoptera frugiperda 9) has already been described (Maier et al., J. Biol. Chem. 1999 (274) 29311-29317).

The kinase assay is carried out in 96-well plates. Each well contains 10 μl of the compound to be tested which is dissolved in assay buffer (40 mM Hepes, pH 7.5, 100 mM NaCl, 1 mM EGTA, 1 mM β-glycerophosphate, 1 mM DTT, 7 mM MgCl 2 and 0.1% BSA; 6% DMSO). 30 μl of lipid vesicles containing 2 ng of PI3Kγ and 24 ng of Gβ 1 γ 2 -His is added in each case. The lipid vesicles in turn are generated by suspending a mixture of PIP 2 (0.7 μg/well), phosphatidylethanolamine (7.5 μg/well), phosphatidyl serine (7 μg/well), sphingomyelin (0.7 μg/well) and phosphatidyl choline (3.2 μg/well) in lipid buffer (assay buffer without DMSO) by ultrasound treatment. After the addition of the lipid vesicles the reaction is started by the addition of 20 μl reaction buffer (40 mM Hepes, pH 7.5, 100 mM NaCl, 1 mM EGTA, 1 mM β-glycerophosphate, 1 mM DTT, 7 mM MgCl 2 and 0.1% BSA; 1 μM ATP and 0.2 μCi [γ- 33 P]-ATP). The reaction mixture is incubated in this way for 2 h and then stopped by the addition of 60 μl of Stop-buffer (40 mM Hepes, pH 7.5, 100 mM NaCl, 1 mM EGTA, 16 mM EDTA, 1 mM β-glycerophosphate, 1 mM DTT). 110 μl of the assay solution is then transferred to Multiscreen filter plates (Millipore, MAIPNOB). The plates are filtered by the application of vacuum and subsequently washed twice with 200 μl/well PBS. The plates are dried at 50° C., allowed to cool, supplemented with 50 μl/well Microscint 20 and counted using a TopCount (Perkin Elmer).

All the compounds shown have an IC 50 value of less than 800 nM in the test.

Indications

It has been found that the compounds of formula 1 are characterised by a variety of possible applications in the therapeutic field. Particular mention should be made of those applications for which the compounds of formula 1 according to the invention are preferably used by virtue of their pharmaceutical activity as PI3-kinase modulators.

Generally speaking, these are diseases in whose pathology PI3-kinases are implicated, particularly inflammatory and allergic diseases. Particular mention should be made of inflammatory and allergic respiratory complaints, inflammatory diseases of the gastrointestinal tract, inflammatory diseases of the motor apparatus, inflammatory and allergic skin diseases, inflammatory eye diseases, diseases of the nasal mucosa, inflammatory or allergic ailments which involve autoimmune reactions or inflammation of the kidneys. The treatment may be symptomatic, adaptive, curative or preventative.

Respiratory complaints deserving special mention would be chronic and/or obstructive respiratory complaints. The compounds of formula 1 according to the invention may, by virtue of their pharmacological properties, bring about a reduction in

Tissue damage Inflammation of the airways bronchial hyperreactivity the process of reconstruction of the lung as a result of inflammation worsening of the disease (progression).

The compounds according to the invention are particularly preferred for preparing a medicament for the treatment of chronic bronchitis, acute bronchitis, bronchitis caused by bacterial or viral infection or fungi or helminths, allergic bronchitis, toxic bronchitis, chronic obstructive bronchitis (COPD), asthma (intrinsic or allergic), pediatric asthma, bronchiectasis, allergic alveolitis, allergic or non-allergic rhinitis, chronic sinusitis, cystic fibrosis or mucoviscidosis, alpha-1-antitrypsin deficiency, cough, pulmonary emphysema, interstitial lung diseases such as e.g. pulmonary fibrosis, asbestosis and silicosis and alveolitis; hyperreactive airways, nasal polyps, pulmonary oedema such as e.g. toxic pulmonary oedema and ARDS/IRDS, pneumonitis of different origins, e.g. radiation-induced or by caused by aspiration or infectious pneumonitis, collagenoses such as lupus eryth, systemic sclerodermy, sarcoidosis or Boeck's disease.

The compounds of formula 1 are also suitable for the treatment of diseases of the skin, such as e.g. psoriasis, contact dermatitis, atopic dermatitis, alopecia greata (circular hair loss), erythema exsudativum multiforme (Stevens-Johnson Syndrome), dermatitis herpetiformis, sclerodermy, vitiligo, nettle rash (urticaria), lupus erythematodes, follicular and surface pyodermy, endogenous and exogenous acne, acne rosacea and other inflammatory or allergic or proliferative skin diseases.

Moreover, the compounds of formula 1 are suitable for therapeutic use in cases of inflammatory or allergic complaints which involve autoimmune reactions, such as e.g. inflammatory bowel diseases, e.g. Crohn's disease or ulcerative colitis; diseases of the arthritis type, such as e.g. rheumatoid or psoriatic arthritis, osteoarthritis, rheumatoid spondylitis and other arthritic conditions or multiple sclerosis.

The following general inflammatory or allergic diseases may also be mentioned, which can be treated with medicaments containing compounds of formula 1:

inflammation of the eye, such as e.g. conjunctivitis of various kinds, e.g. caused by infections with fungi or bacteria, allergic conjunctivitis, irritable conjunctivitis, drug-induced conjunctivitis, keratitis, uveitis diseases of the nasal mucosa, such as e.g. allergic rhinitis/sinusitis or nasal polyps inflammatory or allergic conditions, such as e.g. systemic lupus erythematodes, chronic hepatitis, kidney inflammations such as glomerulonephritis, interstitial nephritis or idiopathic nephrotic syndrome.

Other diseases which may be treated with a drug containing compounds of formula 1 on the basis of their pharmacological activity include toxic or septic shock syndrome, atherosclerosis, middle ear infections (otitis media), hypertrophy of the heart, cardiac insufficiency, stroke, ischaemic reperfusion injury or neurodegenerative diseases such as Parkinson's disease or Alzheimer's.

Combinations

The compounds of general formula 1 may be used on their own or combined with other active substances of formula 1 according to the invention. The compounds of general formula 1 may optionally also be combined with other pharmaceutically active substances. These include, in particular, betamimetics, anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamin-agonists, antiallergic agents, PAF-antagonists and PI3-kinase inhibitors, but also combinations of two or three active substances, i.e.:

Betamimetics with corticosteroids, PDE4-inhibitors, EGFR-inhibitors or LTD4-antagonists, Anticholinergics with betamimetics, corticosteroids, PDE4-inhibitors, EGFR-inhibitors or LTD4-antagonists, Corticosteroids with PDE4-inhibitors, EGFR-inhibitors or LTD4-antagonists PDE4-inhibitors with EGFR-inhibitors or LTD4-antagonists EGFR-inhibitors with LTD4-antagonists.

Examples of preferred betamimetics which may be mentioned include Albuterole, Arformoterole, Bambuterole, Bitolterole, Broxaterole, Carbuterole, Clenbuterole, Fenoterole, Formoterole, Hexoprenaline, Ibuterole, Isoetharine, Isoprenaline, Levosalbutamole, Mabuterole, Meluadrine, Metaproterenole, Orciprenaline, Pirbuterole, Procaterole, Reproterole, Rimiterole, Ritodrine, Salmefamole, Salmeterole, Soterenole, Sulphonterole, Terbutaline, Tiaramide, Tolubuterole, Zinterole, CHF-1035, HOKU-81, KUL-1248 and

3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzyl-sulfonamide 5-[2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one 4-Hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone 1-(2-Fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanole 1-[3-(4-Methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanole 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanole 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanole 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanole 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol 5-Hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one 1-(4-Amino-3-chloro-5-trifluormethylphenyl)-2-tert.-butylamino)ethanol 6-Hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one 6-Hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic acid ethylester)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one 6-Hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic acid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one 8-{2-[1,1-Dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one 6-Hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one 6-Hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one 8-{2-[2-(4-Ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one 8-{2-[2-(4-Ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one 4-(4-{2-[2-Hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric acid 8-{2-[2-(3,4-Difluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-on 1-(4-Ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol 2-Hydroxy-5-(1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino}-ethyl)-benzaldehyde N-[2-Hydroxy-5-(1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino}-ethyl)-phenyl]-formamide 8-Hydroxy-5-(1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]-ethylamino}-ethyl)-1H-quinolin-2-one 8-Hydroxy-5-[1-hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-1H-quinolin-2-one 5-[2-(2-{4-[4-(2-Amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one [3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-5-methyl-phenyl]-urea 4-(2-{6-[2-(2,6-Dichloro-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol 3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulfonamide 3-(3-{7-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-heptyloxy}-propyl)-benzenesulfonamide 4-(2-{6-[4-(3-Cyclopentanesulfonyl-phenyl)-butoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol N-Adamantan-2-yl-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide (R,S)-4-(2-{[6-(2,2-Difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol (R,S)-4-(2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol (R,S)-4-(2-{[4,4-Difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol (R,S)-4-(2-{[6-(4,4-Difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol (R,S)-5-(2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-8-hydroxyquinolin-2(1H)-one (R,S)-[2-({6-[2,2-Difluoro-2-(3-methylphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol 4-(1R)-2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol (R,S)-2-(Hydroxymethyl)-4-(1-hydroxy-2-{[4,4,5l5-tetrafluoro-6-(3-phenylpropoxy)hexyl]amino}ethyl)phenol (R,S)-[5-(2-{[6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-hydroxyphenyl]formamide (R,S)-4-[2-({6-[2-(3-Bromophenyl)-2,2-difluoroethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol (R,S)-N-[3-(1,1-Difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)-phenyl]ethyl}amino)hexyl]oxy}ethyl)phenyl]urea 3-[3-(1,1-difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}ethyl)phenyl]imidazolidine-2,4-dione (R,S)-4-[2-({6-[2,2-difluoro-2-(3-methoxyphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol 5-((1R)-2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one 4-((1R)-2-{[4,4-Difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol (R,S)-4-(2-{[6-(3,3-Difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol (R,S)-(2-{[6-(2,2-Difluoro-2-phenylethoxy)-4,4-difluorohexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol (R,S)-4-(2-{[6-(2,2-difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxy ethyl)-2-(hydroxymethyl)phenol

optionally in racemic form, as enantiomers, diastereomeres or as pharmaceutically acceptable salts, solvates or hydrates. Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.

Examples of preferred anticholinergics which may be mentioned include Tiotropium salts, preferred the bromide salt, Oxitropium salts, preferred the bromide salt, Flutropium salts, preferred the bromide salt, Ipratropium salts, preferred the bromide salt, Glycopyrronium salts, preferred the bromide salt, Trospium salts, preferred the chloride salt, Tolterodin. From the above mentioned salts the pharmaceutically active part is the cation, possible anions are chloride, bromide, iodide, sulfate, phosphate, methansulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulfonate.

Furthermore

2,2-Diphenylpropion acid tropenolester-methobromide

2,2-Diphenylpropion acid scopinester-methobromide

2-Fluor-2,2-Diphenylacetic acid scopinester-methobromide

2-Fluor-2,2-Diphenylacetic acid tropenolester-methobromide

3,3′,4,4′-Tetrafluorbenzil acid tropenolester-Methobromide

3,3′,4,4′-Tetrafluorbenzil acid scopinester-Methobromide

4,4′-Difluorbenzil acid tropenolester-Methobromide

4,4′-Difluorbenzil acid scopinester-Methobromide

3,3′-Difluorbenzil acid tropenolester-Methobromide

3,3′-Difluorbenzil acid scopinester-Methobromide

9-Hydroxy-fluoren-9-carbon acid tropenolester-Methobromide

9-Fluor-fluoren-9-carbon acid tropenolester-Methobromide

9-Hydroxy-fluoren-9-carbon acid scopinester-Methobromide

9-Fluor-fluoren-9-carbon acid scopinester Methobromide

9-Methyl-fluoren-9-carbon acid tropenolesterMethobromide

9-Methyl-fluoren-9-carbon acid scopinesterMethobromide

Benzil acid cyclopropyltropinester-Methobromide

2,2-Diphenylpropion acid cyclopropyltropinester-Methobromide

9-Hydroxy-xanthen-9-carbon acid cyclopropyltropinesterMethobromide

9-Methyl-fluoren-9-carbon acid cyclopropyltropinester-Methobromide

9-Methyl-xanthen-9-carbon acid cyclopropyltropinester-Methobromide

9-Hydroxy-fluoren-9-carbon acid cyclopropyltropinester-Methobromide

4,4′-Difluorbenzil acid methylestercyclopropyltropinester-Methobromide

9-Hydroxy-xanthen-9-carbon acid tropenolester-Methobromide

9-Hydroxy-xanthen-9-carbon acid scopinester Methobromide

9-Methyl-xanthen-9-carbon acid tropenolester-Methobromide

9-Methyl-xanthen-9-carbon acid scopinesterMethobromide

9-Ethyl-xanthen-9-carbon acid tropenolester Methobromide

9-Difluormethyl-xanthen-9-carbon acid tropenolester-Methobromide

9-Hydroxymethyl-xanthen-9-carbon acid scopinester-Methobromide

Examples of preferred corticosteroids which may be mentioned include Beclomethasone, Betamethasone, Budesonide, Butixocorte, Ciclesonide, Deflazacorte, Dexamethasone, Etiprednole, Flunisolide, Fluticasone, Loteprednole, Mometasone, Prednisolone, Prednisone, Rofleponide, Triamcinolone, RPR-106541, NS-126 and

6,9-Difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-dien-17-carbothion acid (S)-fluoromethylester 6,9-Difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-dien-17-carbothion acid (S)-(2-oxo-tetrahydro-furan-3S-yl)ester, 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tertamethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carboxylic acid cyanomethyl ester

optionally in racemic form, as enantiomers, diastereomeres or as pharmaceutically acceptable salts, solvates or hydrates. Examples for preferred salts and derivatives are alkali salts, i.e. sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogenphosphates, palmitates, pivalates or furoates.

Examples of preferred PDE4-inhibitors which may be mentioned include Enprofylline, Theophylline, Roflumilaste, Ariflo (Cilomilast), Tofimilaste, Pumafentrine, Lirimilaste, Arofylline, Atizorame, Oglemilastum, D-4418, Bay-198004, BY343, CP-325,366, D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585, V-11294A, CI-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and

N-(3,5-Dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide (−)p-[(4aR*,10bS*)-9-Ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide (R)-(+)-1-(4-Bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidon 3-(Cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N-2-cyano-5-methyl-isothioureido]benzyl)-2-pyrrolidone cis[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carbon acid] 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one cis[4-Cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol] R)-(+)-Ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yliden]acetate (S)-(−)-Ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yliden]acetate 9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine 9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine

optionally in racemic form, as enantiomers, diastereomeres or as pharmaceutically acceptable salts, solvates or hydrates. Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.

Examples of preferred LTD4-antagonists which may be mentioned include Montelukaste, Pranlukaste, Zafirlukaste, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321 and

1-(((R)-(3-(2-(6,7-Difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-acetic acid, 1-(((1(R)-3(3-(2-(2,3-Dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid [2-[[2-(4-tert-Butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid

optionally in racemic form, as enantiomers, diastereomeres or as pharmaceutically to acceptable salts, solvates or hydrates. Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate. Further examples for optionally preferred salts and derivatives are alkali salts, i.e. sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogenphosphates, palmitates, pivalates or furoates.

Examples of preferred EGFR-inhibitors which may be mentioned include Cetuximabe, Trastuzumabe, ABX-EGF, Mab ICR-62 and

4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazoline 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazoline 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazoline 4-[(R)-(1-Phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-chinazoline 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-chinazoline 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-chinazoline 4-[(R)-(1-Phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazoline 4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-chinazoline 4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-chinazoline 4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-chinazoline 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-chinazoline 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-chinazoline 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-chinazoline 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-chinazoline 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-chinazoline 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazoline 4-[(3-Ethinyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-chinazoline 4-[(3-Chlor-4-fluorphenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-chinazoline 4-[(R)-(1-Phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine 3-Cyano-4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-chinoline 4-{[3-Chlor-4-(3-fluor-benzyloxy)-phenyl]amino}-6-(5-{[(2-methansulfonyl-ethyl)amino]methyl}-furan-2-yl)chinazoline 4-[(R)-(1-Phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-chinazoline 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-chinazoline 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-chinazoline 4-[(3-Ethinyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-methansulfonylamino-cyclohexan-1-yloxy)-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(dimethylamino)sulfonylamino]-cyclohexan-1-yloxy}-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulfonylamino]-cyclohexan-1-yloxy}-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methansulfonylamino-ethoxy)-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulfonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-ethansulfonylamino-cyclohexan-1-yloxy)-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-ethoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-chinazoline 4-[(3-Ethinyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-chinazoline 4-[(3-Ethinyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-chinazoline 4-[(3-Ethinyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-chinazoline 4-[(3-Ethinyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-chinazoline 4-[(3-Ethinyl-phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-chinazoline 4-[(3-Ethinyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-chinazoline 4-[(3-Ethinyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-chinazoline 4-[(3-Ethinyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-methansulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[trans-4-(N-methansulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-methoxy-chinazoline 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-chinazoline

optionally in racemic form, as enantiomers, diastereomeres or as pharmaceutically acceptable salts, solvates or hydrates. Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.

Examples of preferred dopamin antagonists which may be mentioned include Bromocriptine, Cabergoline, Alpha-Dihydroergocryptine, Lisuride, Pergolide, Pramipexole, Roxindole, Ropinirole, Talipexole, Terguride and Viozane, optionally in racemic form, as enantiomers, diastereomeres or as pharmaceutically acceptable salts, solvates or hydrates. Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate, to hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate und hydro-p-toluenesulfonate.

Examples of preferred antiallergic agents which may be mentioned include Epinastine, Cetirizine, Azelastine, Fexofenadine, Levocabastine, Loratadine, Mizolastine, Ketotifene, Emedastine, Dimetindene, Clemastine, Bamipine, Cexchlorpheniramine, Pheniramine, Doxylamine, Chlorphenoxamine, Dimenhydrinate, Diphenhydramine, Promethazine, Ebastine, Desloratidine and Meclozine, optionally in racemic form, as enantiomers, diastereomeres or as pharmaceutically acceptable salts, solvates or hydrates. Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate und hydro-p-toluenesulfonate.

Examples of preferred PAF antagonists which may be mentioned include

4-(2-Chlorphenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-1-yl]-6H-thieno-[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine 6-(2-Chlorphenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclo-penta-[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine

optionally in racemic form, as enantiomers, diastereomeres or as pharmaceutically acceptable salts, solvates or hydrates. Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.

Formulations

The compounds according to the invention may be administered by oral, transdermal, inhalative, parenteral or sublingual route. The compounds according to the invention are present as active ingredients in conventional preparations, for example in compositions consisting essentially of an inert pharmaceutical carrier and an effective dose of the active substance, such as for example tablets, coated tablets, capsules, lozenges, powders, solutions, suspensions, emulsions, syrups, suppositories, transdermal systems etc. An effective dose of the compounds according to the invention is between 0.1 and 5000, preferably between 1 and 500, more preferably between 5-300 mg/dose for oral administration, and between 0.001 and 50, preferably between 0.1 and 10 mg/dose for intravenous. subcutaneous or intramuscular administration. For inhalation, according to the invention, solutions containing 0.01 to 1.0, preferably 0.1 to 0.5% active substance are suitable. For administration by inhalation the use of powders, ethanolic or aqueous solutions is preferred. It is also possible to use the compounds according to the invention as a solution for infusion, preferably in a physiological saline or nutrient saline solution.

The compounds according to the invention may be used on their own or in conjunction with other active substances according to the invention, optionally also in conjunction with other pharmaceutically active substances. Suitable formulations include, for example, tablets, capsules, suppositories, solutions, syrups, emulsions or dispersible powders. Corresponding tablets may be obtained for example by mixing the active substance(s) with known excipients, for example inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrants such as maize starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores produced to analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.

Syrups containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

Solutions for injection are prepared in the usual way, e.g. with the addition of preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, and transferred into injection vials or ampoules.

Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.

A therapeutically effective daily dose is between 1 and 2000 mg, preferably 10-500 mg per adult.

The Examples which follow illustrate the present invention without restricting its scope:

Examples of Pharmaceutical Formulations

The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, granulated while wet and dried. The granulate, the rest of the corn starch and the magnesium stearate are screened and mixed together. The mixture is compressed to form tablets of a suitable shape and size.

The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened. The sodium-carboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.

The active substance, corn starch, lactose and polyvinylpyrrolidone are thoroughly mixed and moistened with water. The moist mass is pushed through a screen with a 1 mm mesh size, dried at about 45° C. and the granules are then passed through the same screen. After the magnesium stearate has been mixed in, convex tablet cores with a diameter of 6 mm are compressed in a tablet-making machine. The tablet cores thus produced are coated in a known manner with a covering consisting essentially of sugar and talc. The finished coated tablets are polished with wax

The substance and corn starch are mixed and moistened with water. The moist mass is screened and dried. The dry granules are screened and mixed with magnesium stearate. The finished mixture is packed into size 1 hard gelatine capsules.

The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.

The hard fat is melted. At 40° C. the ground active substance is homogeneously dispersed. It is cooled to 38° C. and poured into slightly chilled suppository moulds.

Distilled water is heated to 70° C. Hydroxyethyl-cellulose is dissolved therein with stirring. After the addition of sorbitol solution and glycerol the mixture is cooled to ambient temperature. At ambient temperature, sorbic acid, flavouring and substance are added. To eliminate air from the suspension it is evacuated with stirring.